The 3-year follow-up of the phase III CheckMate 9ER trial demonstrates superior outcomes with the combination of nivolumab plus cabozantinib vs the former standard-of-care sunitinib as first-line treatment of advanced or metastatic renal cell carcinoma.¹ These benefits were achieved with the combination regardless of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores and PD-L1 status. This represents the longest follow-up of an immunotherapy plus tyrosine kinase inhibitor regimen in renal cell carcinoma.

The findings demonstrate superior overall survival, progression-free survival, overall response rates, duration of response, and complete response rates for nivolumab plus cabozantinib vs sunitinib, at a minimum follow-up of 36.5 months and a median follow-up of 44 months. These updates were presented by Mauricio Burotto, MD, Medical Director, Bradford Hill Clinical Research Center, Santiago, Chile, at the 2023 ASCO Genitourinary (GU) Cancers Symposium.¹

“These results reinforce the importance of this immunotherapy plus tyrosine kinase inhibitor regimen for patients and its potential to help change survival expectations.”

— Mauricio Burotto, MD

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“Despite the progress made through science and medicine, there remains a need for treatment options that can durably extend survival for patients with metastatic renal cell carcinoma, especially those classified as higher risk,” said Dr. Burotto. “With these updated results from CheckMate 9ER, we’ve now seen nivolumab in combination with cabozantinib durably extend survival and sustain response benefits compared with sunitinib for over 3 years, regardless of patients’ risk classification. These results reinforce the importance of this immunotherapy plus tyrosine kinase inhibitor regimen for patients and its potential to help change survival expectations.”

Toni K. Choueiri, MD

The findings related to PD-L1 status were presented separately in a poster session by Toni K. Choueiri, MD, Director of the Lark Center for Genitourinary Oncology, Dana-Farber Cancer Center, Boston.² “The results in this study are specific to nivolumab plus cabozantinib,” Dr. Choueiri said. “Nivolumab plus cabozantinib should be used in the first line for all patients with advanced renal cell carcinoma, and PD-L1 status should not drive clinical decisions. The combination has shown an overall survival advantage [over sunitinib] with an improvement in quality of life. People [treated with the combination] are living longer and healthier lives,” he said.

Study Details

CheckMate 9ER was an open-label, randomized, multinational phase III trial that compared the combination of nivolumab plus cabozantinib (n = 323) vs sunitinib (n = 328) as first-line treatment in 651 patients with previously untreated advanced or metastatic renal cell carcinoma. Among all patients enrolled in the trial, IMDC risk categories were favorable (22%), intermediate (58%), and poor risk (20%). A total of 25% of the study population had PD-L1–positive disease, as reflected by the presence of PD-L1 in at least 1% of tumor biopsies. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and objective response rate.

At a median follow-up of 44.0 months, nivolumab plus cabozantinib continued to show superior outcomes vs sunitinib. No new safety signals emerged with extended follow-up.

In the overall study population, the immunotherapy plus tyrosine kinase inhibitor combination achieved a 30% reduction in the risk of death vs sunitinib. Median overall survival was 49.5 months vs 35.5 months, respectively. Median overall survival improved by 11.8 months since the previous data cutoff, at a median follow-up of 32.9 months. With extended follow-up, the median progression-free survival was 16.6 months vs 8.4 months with sunitinib, a doubling of benefit for the combination.

At extended follow-up, the combination of nivolumab plus cabozantinib maintained overall response rates and duration of response rates. Nearly twice as many patients responded to the experimental arm: 55.7% vs 28.4% with sunitinib. Median duration of response was 23.1 months with the combination vs 15.2 months with sunitinib. Complete response rates were also sustained: 12.4% with the combination vs 5.2% with sunitinib.

Treatment-related adverse events were reported in 97% of those treated with nivolumab plus cabozantinib vs 93% of those who received sunitinib. Grade 3 or higher treatment-related adverse events were reported in 67% vs 55%, respectively.

Analysis of PD-L1 Status

An exploratory post hoc analysis from CheckMate 9ER was presented at a poster session by Dr. Choueiri.² At a median follow-up of 44 months, improvements were observed in both median overall and progression-free survival with nivolumab plus cabozantinib regardless of PD-L1 status.

Progression-free and overall survival were evaluated by tumor PD-L1 expression (< 1% or ≥ 1%), CD8-positive (low, medium, high by tertiles), and CD8 topology phenotype (cold, excluded, inflamed). These endpoints were assessed for association using Kaplan-Meier methods with log-rank test (PD-L1 and CD8), and Cox proportional hazard models (CD8). Biomarkers previously found to be predictive of anti–PD-L1 plus anti-VEGF outcomes, including established gene-expression signatures, were not necessarily predictive of efficacy with anti–PD-1 plus anti-VEGF targeted therapy, suggesting that key determinants of response to anti–PD-1 vs anti–PD-L1 therapies may differ.

Additional Commentary

Commenting on the CheckMate 9ER results, Sandy Liu, MD, Medical Director of Genitourinary Medical Oncology at City of Hope, Orange County, said: “Based on the data from CheckMate 9ER, nivolumab plus cabozantinib is a standard of care and should be considered for all patients in the front-line setting for advanced renal cell carcinoma regardless of IMDC risk group or PD-L1 status.”

Sandy Liu, MD

Farshid Sadeghi, MD

“These data are the longest follow-up data available for any checkpoint inhibitor plus tyrosine kinase inhibitor combination of 44 months. The data showed a sustained survival curve of 49.5 months with nivolumab plus cabozantinib vs 35.5 months with sunitinib, representing a 30% reduction of disease progression or death,” Dr. Liu continued.

“Additionally, I would like to highlight results from CheckMate 9ER, which offer a balance of efficacy, safety, and quality of life for patients,” she said.

Farshid Sadeghi, MD, Medical Director of Genitourinary Center and a urologic oncologist at City of Hope, Phoenix agreed. “In the metastatic setting, nivolumab plus cabozantinib should be the standard of care for all eligible patients with renal cell carcinoma. The higher cost of combined systemic therapy is warranted given the survival benefit,” he noted. 

DISCLOSURE: The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical and cofunded by Exelixis, Ipsen Pharma SAS, and Takeda. Dr. Burotto has received honoraria from AstraZeneca, BMS, Merck, Novartis, and Roche; and participated on a data safety monitoring board at AstraZeneca, BMS, Merck, and Roche. Dr. Choueiri reported financial and/or nonfinancial relationships (including potential reimbursements for travel and meals) with Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, -AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Janssen, Michael J. Hennessy Associates, Navinata Healthcare, the National Comprehensive Cancer Network, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds international patents for biomarkers and has other relationships with ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel (medical writing assistance); and holds stock or other ownership interests in Pionyr Immunotherapeutics and Tempest Therapeutics. Dr. Liu has received honoraria from Exelixis, Esai, SeaGen, Merck, and EMD Serono; has served as a consultant or advisor to Exelixis and SeaGen; and has served on a speakers bureau for Exelixis, EMD Serrono, and SeaGen. Dr. Sadeghi reported no conflicts of interest.

REFERENCES

1. Burotto M, Powles T, Escudier B, et al: Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma: 3-year follow-up from the phase 3 CheckMate 9ER trial. 2023 ASCO GU Cancers Symposium. Abstract 603. Presented February 18, 2023.

2. Choueiri TK, Motzer RJ, Powles T, et al: Biomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma. 2023 ASCO GU Cancers Symposium. Abstract 608. Presented February 18, 2023.